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Review
. 2020 May;17(5):433-450.
doi: 10.1038/s41423-020-0412-0. Epub 2020 Apr 1.

Neutrophil chemoattractant receptors in health and disease: double-edged swords

Mieke Metzemaekers  1 , Mieke Gouwy  1 , Paul Proost  2
Affiliations
Review

Neutrophil chemoattractant receptors in health and disease: double-edged swords

Mieke Metzemaekers et al. Cell Mol Immunol. 2020 May.

Abstract

Neutrophils are frontline cells of the innate immune system. These effector leukocytes are equipped with intriguing antimicrobial machinery and consequently display high cytotoxic potential. Accurate neutrophil recruitment is essential to combat microbes and to restore homeostasis, for inflammation modulation and resolution, wound healing and tissue repair. After fulfilling the appropriate effector functions, however, dampening neutrophil activation and infiltration is crucial to prevent damage to the host. In humans, chemoattractant molecules can be categorized into four biochemical families, i.e., chemotactic lipids, formyl peptides, complement anaphylatoxins and chemokines. They are critically involved in the tight regulation of neutrophil bone marrow storage and egress and in spatial and temporal neutrophil trafficking between organs. Chemoattractants function by activating dedicated heptahelical G protein-coupled receptors (GPCRs). In addition, emerging evidence suggests an important role for atypical chemoattractant receptors (ACKRs) that do not couple to G proteins in fine-tuning neutrophil migratory and functional responses. The expression levels of chemoattractant receptors are dependent on the level of neutrophil maturation and state of activation, with a pivotal modulatory role for the (inflammatory) environment. Here, we provide an overview of chemoattractant receptors expressed by neutrophils in health and disease. Depending on the (patho)physiological context, specific chemoattractant receptors may be up- or downregulated on distinct neutrophil subsets with beneficial or detrimental consequences, thus opening new windows for the identification of disease biomarkers and potential drug targets.

Keywords: G protein-coupled receptors; Neutrophils; chemoattractant; chemokine; leukocyte migration.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Regulation of neutrophil migration and activation by chemoattractants. Inflammation or tissue injury leads to increased G-CSF production, thus stimulating neutrophil mobilization into the peripheral blood. Interactions between selectins and their receptors facilitate the initial rolling of the neutrophil along the vascular endothelium. A chemoattractant gradient determines the direction of neutrophil migration. Activation of chemoattractant receptors induces the upregulation and activation of integrins. Binding of integrins to their ligands enables tight adhesion, eventually leading to trans- or paracellular migration. At the site of infection, neutrophils can phagocytose foreign material, including pathogens, produce reactive oxygen/nitrogen species (ROS/RNS) and release degradative enzymes and microbicidal agents (via degranulation) and neutrophil extracellular traps (NETs)
Fig. 2
Fig. 2
Examples of potential chemoattractant complementarity and collaboration. Different chemoattractant families and their receptors may fulfill complementary roles during neutrophil migration and activation in vivo. a Migrating neutrophils can discriminate between intermediate-target (chemokines and LTB4) and end-target (C5a and fMLF) chemoattractants and will eventually follow end-target signals. b Locally produced chemoattractants may preferentially stimulate neutrophil transmigration via the trans- or paracellular route. c Chemokines and PAF act as priming agents that push the neutrophil towards a state of ‘high alert’, resulting in a more aggressive response upon subsequent exposure to activating signals such as those from C5a, fMLF and LTB4
Fig. 3
Fig. 3
Downstream effects of chemoattractant-induced GPCR activation. Activation of chemoattractant receptors by their cognate ligands evokes a conformational change and the exchange of guanosine diphosphate (GDP) for guanosine trisphosphate (GTP), followed by dissociation of the heterotrimeric G protein into a Gαi subunit and a Gβγ dimer. The Gαi subunit mediates the inhibition of adenylyl cyclase (AC), resulting in a reduction in intracellular cyclic adenosine monophosphate (cAMP) concentrations. The Gβγ dimer initiates two parallel signaling cascades. Activation of phospholipase Cβ (PLCβ) enables the processing of phosphatidylinositol (4,5)-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) and the downstream activation of protein kinase C (PKC) isoforms. Second, the activation of phosphoinositide 3-kinase γ (PI3Kγ) facilitates the conversion of PIP2 into phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and the downstream activation of extracellular signal–regulated kinases (ERK) and phosphokinase B (Akt). Activation of Src kinases presumably occurs via an independent yet uncharacterized pathway (indicated by question marks). Phosphorylation of the receptor at the COOH-terminus enables binding of the β-arrestin adaptor proteins that uncouple the receptor during conventional G protein-dependent intracellular events
Fig. 4
Fig. 4
Regulation of chemokine receptor expression by neutrophils. Naive neutrophils, freshly released from the bone marrow, display high levels of CXCR1 and CXCR2, which are the two major chemokine receptors involved in the trafficking of human neutrophils. Exposure to endogenous or exogenous inflammatory mediators may induce the upregulation of additional chemokine receptors, e.g., CCRs and CXCR3. Prolonged stimulation or exposure to high chemokine concentrations induces the downregulation of chemokine receptors. Consequently, highly activated, infiltrated cells are characterized by low CXCR1 and CXCR2 expression levels. Neutrophil aging is accompanied by the upregulation of CXCR4 expression, thereby facilitating a return of the cell to the bone marrow, which contains high levels of CXCL12
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